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MKK6 binds and regulates expression of Parkinson’s disease‐related protein LRRK2
Author(s) -
Hsu Cindy H.,
Chan Diane,
Greggio Elisa,
Saha Shamol,
Guillily Maria D.,
Ferree Andrew,
Raghavan Kesav,
Shen Grace C.,
Segal Lilach,
Ryu Hoon,
Cookson Mark R.,
Wolozin Benjamin
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06568.x
Subject(s) - lrrk2 , gene knockdown , kinase , microbiology and biotechnology , biology , cytoplasm , phosphorylation , rna interference , genetics , mutation , gene , rna
J. Neurochem. (2010) 112 , 1593–1604. Abstract Mutations in leucine‐rich repeat kinase 2 (LRRK2) are prevalent causes of late‐onset Parkinson’s disease. Here, we show that LRRK2 binds to MAPK kinases (MKK) 3, 6, and 7, and that LRRK2 is able to phosphorylate MKK3, 6 and 7. Over‐expression of LRRK2 and MKK6 increased the steady state levels of each protein beyond that observed with over‐expression of either protein alone. Co‐expression increased levels of MKK6 in the membrane more than in the cytoplasm. The increased expression of LRRK2 and MKK6 requires MKK6 activity. The disease‐linked LRRK2 mutations, G2019S, R1441C and I2020T, enhance binding of LRRK2 to MKK6. This interaction was further supported by in vivo studies in C. elegans . RNAi knockdown in C. elegans of the endogenous orthologs for MKK6 or p38, sek‐1 and pmk‐1, abolishes LRRK2‐mediated protection against mitochondrial stress. These results were confirmed by deletion of sek‐1 in C. elegans . These data demonstrate that MKKs and LRRK2 function in similar biological pathways, and support a role for LRRK2 in modulating the cellular stress response.